This invention is directed to novel crystal forms and improved synthetic methods for 9-substituted hypoxanthine compounds, particularly the 9-substituted hypoxanthine derivative 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid monopotassium salt (AIT-082), also designated N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, monopotassium salt.
There is a need for compounds that are bifunctional and that can interact with multiple receptors on the surface of different cell types. There is also a particular need for compounds that bypass the blood-brain barrier so that the activities of such compounds can be exerted in the central nervous system, such as for the treatment of diseases such as Alzheimer""s disease, amyotrophic lateral sclerosis (Lou Gehrig""s disease), and other neurodegenerative diseases.
A number of such compounds and methods for synthesizing them are disclosed in U.S. Pat. No. 5,091,432 to Glasky, incorporated herein by this reference. This includes a number of bifunctional compounds that cross the blood-brain barrier. Exemplary multifunctional compounds are formed from a first biologically active chemical moiety having immunological activity and a second biologically active chemical moiety having neurological activity. An exemplary immunologically active chemical moiety is hypoxanthine or purin-6(1H)-one. An additional benefit to the utilization of hypoxanthine is its structural relationship to inosine, the only purine known to cross the blood brain barrier. Hypoxanthine can be linked by a chemical bridging group, such as propionic acid or butyric acid, to a wide variety of neurologically active chemical moieties to produce a variety of compounds including 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid, also referred to as N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide.
Although synthetic methods for these bifunctional compounds, including 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid or N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide hydrochloride were described in U.S. Pat. No. 5,091,432 to Glasky, there is a need for an improved synthetic method for these compounds. There is a particular need for a more efficient synthesis that provides higher yields and a more consistent synthesis that provides fewer side reactions as well as providing a pure and stable product.
During compound synthesis a variety of different crystalline forms of the same drug substance (polymorphism) may result. The existence of such polymorphisms is significant because different crystalline forms may have different solubility in water and thus different degrees of bioavailability in terms of pharmacokinetics (solubility) and pharmacodynamics of the compound. Therefore, compound polymorphism must be carefully checked as individual crystal structures could lead to differences in bioavailability. Therefore, there is a particular need for an analysis of the polymorphic forms of compound products and their interconversion processes. There is also a particular need for methods for producing the most stable form of compounds such as 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid monopotassium salt or N4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monopotassium salt and for converting other crystalline and stable forms of the compound into the most stable form. All of the stable forms of this compound are pharmaceutically acceptable.
One aspect of the present invention is a crystalline form of the monopotassium salt of N-4-carboxyphenyl-3(6-oxohydropurin-9-yl) propanamide monohydrate that has a solubility of about 5% (w/v) in water at 25xc2x0 C., has an infrared spectrum peak from 1674.1 cmxe2x88x921 to about 1675.7 cmxe2x88x921 as measured by Fourier-transform infrared spectroscopy, and that has an X-ray powder pattern that is distinct from the X-ray powder pattern of any other crystalline form of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monopotassium salt, the crystalline form being designated Type I.
Another aspect of the present invention is a crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate that has a solubility of about 10% (w/v) in water at 25xc2x0 C., has an infrared spectrum peak of about 1693.4 cmxe2x88x921 as measured by Fourier-transform infrared spectroscopy, and that has an X-ray powder pattern that is distinct from the X-ray powder pattern of any other crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, the crystalline form being designated Type II.
Yet another aspect of the present invention is a substantially anhydrous crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate that has less than about 1.0% water as measured by the Karl Fischer titration process, that has an infrared spectrum peak of about 1687.8 cmxe2x88x921 and that has an X-ray powder pattern that is distinct from the X-ray powder pattern of any other crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, the crystalline form being designated Type III.
Another aspect of the present invention is a method for synthesizing the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate comprising the steps of:
(1) reacting the free acid of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide with potassium hydroxide in water; and
(2) precipitating the product of step (1) with ethanol to yield the Type I crystalline form.
Yet another aspect of the present invention is another method for synthesizing the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate comprising the steps of:
(1) reacting N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide ethyl ester monoacetate with potassium hydroxide to produce N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide in a crystalline form distinct from Type I; and
(2) reacting the product of step (1) with a mixture of ethanol and water containing a low concentration of potassium hydroxide to yield the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate.
Still another aspect of the present invention is a method for converting a distinct crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, designated Type II, to the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate comprising the step of equilibrating the crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide designated Type II with water vapor at a temperature in a range from about 60xc2x0 C. to about 80xc2x0 C. for a time period of from about 36 hours to about 60 hours to yield the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate.
Preferably, in this method, the temperature is about 70xc2x0 C. and the time period is about 48 hours.
Yet another aspect of the present invention is a method for converting a distinct crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide, designated Type III, to the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate comprising the step of equilibrating the crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide designated Type III with water vapor at about 25xc2x0 C. to yield the Type I crystalline form of the monopotassium salt of N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monohydrate.